Document 6481487

0749-5161/02/1801-0036
Vol. 18, No. 1
Printed in U.S.A.
PEDIATRIC EMERGENCY CARE
Copyright © 2002 by Lippincott Williams & Wilkins, Inc.
Hyperinsulinemia/euglycemia therapy for
calcium channel blocker poisoning
EDWARD W. BOYER, MD, PhD, PETER A. DUIC, MD, ADELAIDE EVANS, MD
INTRODUCTION
presentation, was 1094 ng/mL; a corresponding norverapamil level
was 1253 ng/ mL (therapeutic concentration: 100–600 ng/mL) (6).
Patient 3. A 48-year-old nondiabetic male with hypertension,
chronic obstructive pulmonary disease, congestive heart failure,
and depression, ingested an unknown amount of extended-release
diltiazem in a witnessed ingestion. He became hemodynamically
unstable in the emergency department, failing to respond to calcium, IV fluids, dopamine, and dobutamine. He received an insulin
infusion at a rate of 75 IU/kg/h, which improved his blood pressure
to 115/60 mmHg. All pressors were discontinued within 30 minutes of insulin administration. The patient received the insulin infusion for 5 hours. The patient also received 10 g/h of glucose supplementation (5).
Patient 4. A 34-year-old nondiabetic female with hypertension and renal failure ingested 0.86 mg/kg amlodipine tablets. One
hour after the ingestion, she became hypotensive with a systolic
blood pressure of 40 mmHg and pulse of 60. Because of her history of renal failure, treating physicians did not administer calcium, providing instead activated charcoal, IV fluids, dopamine,
dobutamine, norepinephrine, and glucagon. She received 35 U/h
of insulin as a continuous IV infusion. Because her initial capillary
glucose was 325 mg/dL, she received no supplemental dextrose.
Instead, her serum glucose was measured every 15 minutes for
1 hour, and every 30 minutes thereafter. Her blood pressure rose
to 150/60 mmHg within 30 minutes of the insulin infusion. When
dopamine, norepinephrine, and glucagon were stopped 45 minutes
after HIE therapy began, her blood pressure remained unchanged.
The insulin infusion was discontinued after 6 hours (5).
Patient 5. A 31-year-old male ingested 71 mg/kg of sustained release verapamil. The patient’s had systolic blood pressure 70 mmHg
with a pulse of 50; an EKG demonstrated 3rd degree block. The patient, who was orotracheally intubated, was estimated to have an ejection fraction of 10% based upon an echocardiogram. He received activated charcoal, IV fluids, calcium chloride, glucagon, and atropine.
Along with 8g/h of dextrose, insulin was administered (10 U bolus,
followed by a continuous infusion of up to 10 U/h). Blood pressure increased to 150/70 mmHg, the ejection fraction improved to 50%, and
the patient converted to normal sinus rhythm with a rate of 84 beats
per minute. Because of oliguria, dopamine was infused at a rate of
2.5 ug/kg/h. Dopamine and insulin infusions were discontinued at 18
and 22 hours, respectively. A peak serum verapamil concentration was
3710 ng/mL, and a norverapamil concentration was 487 ng/mL (6).
Calcium channel blocker (CCB) overdose remains a significant
cause of poisoning death (1). Conventional therapy consisting of
intravenous (IV) fluids, calcium, dopamine, dobutamine, norepinephrine, and glucagon often fails to improve hemodynamic
parameters in severely intoxicated patients (2). Because of these
failures, efforts have focused on the development of novel treatments for this poisoning (3, 4). One, hyperinsulinemia/euglycemia
(HIE) therapy, has produced striking benefit (5, 6). This review
provides a synopsis of pediatric and adult CCB-poisoned patients
treated with this therapy, describes its mechanism of action, and
proposes indications and dosing for HIE therapy.
CASES
Patient 1. A 5-month-old female weighing 5.5 kg was inadvertently given 20 mg of nifedipine. The infant developed systolic blood
pressures of 50 mmHg within 20 minutes and required ventilatory assistance. The patient received calcium chloride, glucagon, dopamine,
epinephrine, phenylephrine, and milrinone. Despite these treatments,
the patient remained hypotensive with a systolic blood pressure of 50
mmHg; her arterial pH was 7.05. A continuous insulin infusion was
begun at 1 U/kg/h. One half hour after starting the insulin infusion,
the patient’s systolic blood pressure increased to 80 to 90 mmHg.
Glucagon and phenylephrine were discontinued at 30 minutes and
2 hours, respectively, and epinephrine, dopamine, and milrinone
were discontinued by 72 hours, 90 hours, and 90 hours, respectively.
After 96 hours, insulin was discontinued. The patient developed
anuric renal failure, but this condition resolved within 30 days (7).
Patient 2. A 14-year-old female ingested 30 mg/kg of sustained
release verapamil over a 6-hour period. Upon presentation, her
blood pressure was 69/24 mmHg, and her pulse was 56 with a 3rd
degree heart block. She received activated charcoal; after an initial
response to calcium gluconate and atropine, hypotension returned.
She received insulin (a 10 U bolus, followed by a continuous infusion at a rate of 12 U/h) and 6g/h of a dextrose infusion. After 2
hours, the insulin infusion rate was increased to 20 U/h. Her blood
pressure increased to 120 mmHg. She received no other medications.
The insulin and dextrose infusions were discontinued at 9 and 12
hours, respectively. A serum verapamil concentration, drawn upon
From the Departments of Emergency Medicine, University of Massachusetts—Memorial Health Center, Worcester, Massachusetts (E.W.
Boyer), and Brigham and Women’s Hospital, Harvard Medical School,
Boston, Massachusetts (P.A. Duic, A. Evans).
Address for reprints: Edward W Boyer, MD, PhD, Department of Emergency Medicine, University of Massachusetts—Memorial Medical Center,
55 Lake Avenue North, Worcester, MA 01655.
Key Words: Hyperinsulinemia, euglycemia, calcium channel blockers,
overdose, poisoning
DISCUSSION
The clinical features of CCB toxicity arise from blockade of Ltype calcium channels in myocardial cells, smooth muscle cells in the
vasculature, and beta-islet cells of the pancreas (8). Antagonism of
these channels produces conduction delay, bradycardia, peripheral
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Vol. 18, No. 1
HYPERINSULINEMIA/EUGLYCEMIA THERAPY
vasodilatation, hypoinsulinemia, and hyperglycemia. Metabolic acidosis, a common clinical finding, is due to lactic acid and arises from
poor perfusion or deranged metabolism of lactate (9, 10).
Hypoinsulinemia appears to be a critical factor in CCB overdose
(11). Myocytes, in an unstressed aerobic state, oxidize free fatty
acids for metabolic energy (8, 6). In shock states, such as in CCB
toxicity, myocytes switch to glucose utilization for fuel (8, 6). Hypoinsulinemia may prevent glucose uptake by myocytes, with ensuing loss of inotropy and decreased peripheral vascular resistance
(6). As tissue perfusion falls, the decreased delivery of glucose deprives myocytes of needed fuel. Continuation of this cycle leads to
hemodynamic deterioration, shock, and ultimately death.
The exact mechanism of action of HIE therapy is poorly defined.
Hyperinsulinemia/euglycemia therapy improves inotropy and peripheral vascular resistance and reverses acidosis, possibly by improving
carbohydrate uptake and utilization by myocytes (8, 6). In addition,
HIE therapy may promote the metabolism of lactate, thereby limiting
the metabolic acidosis common in CCB poisoning. In general, the effectiveness of HIE therapy is limited to improvements in arterial
blood pressure and acidosis, with beneficial effects frequently occurring within 20 to 45 minutes of insulin administration.
Insulin has a variable effect on cardiac conduction. Among reported cases, only 2 patients converted from 3rd degree heart block
to normal sinus rhythm after this therapy was begun (6). Unfortunately, the temporal relationship between HIE and conversion is
unclear. Because HIE often fails to correct bradycardia, heart
block, and intraventricular conduction delay, other therapeutic
modalities such as calcium administration should be aggressively
pursued in patients with conduction disturbances.
Cases describing the failure of HIE therapy are infrequent (12,
13). In both, HIE therapy was not begun until late in the patients’
courses, with 1 patient not receiving HIE until after ACLS protocols had been exhausted (13). These findings suggest that HIE therapy should not be delayed, although specific data to confirm this
recommendation are lacking.
Because each of these cases is drawn from case reports and
poorly controlled case series, considerable variation exists in the
indications for therapy, insulin dosing and duration, as well as for
glucose and potassium supplementation. Our recommendations for
the indications and dosing of HIE therapy are presented in Table 1.
It must be noted, however, that these guidelines are proposals only;
they have not been validated by clinical trials. At present, HIE is re-
TABLE 1
Protocol for hyperinsulinemia/euglycemia in the treatment of calcium
channel antagonist poisoning
1. Measure bedside capillary glucose; measure electrolytes, including
potassium:
a. If glucose 200, administer 1 ampule D50 (for adults); or 0.25
gm/kg dextrose as a D25 solution (for children).
b. If potassium 2.5 mEq/dL, administer 40 mEq.
2. Administer intravenous bolus of insulin (1 U/kg).
For adult and pediatric patients, start D10 1/2 NSS infusion at a rate equal
to 80% of maintenance rate.
Add 250 U regular insulin to 250 cc normal saline to make a solution of
1 U/mL. Infuse this solution at a rate of 0.5 U/kg/hr. Infusion rate may
be increased to 1 U/kg/hr depending upon clinical response. Targets for
therapy are systolic blood pressure greater than 100 mm/Hg and heart
rate greater than 50.
Recheck serum capillary glucose every 20 minutes for the first hour of the
insulin infusion, and hourly thereafter. Recheck serum potassium
hourly; replete if 2.5 mEq/dL.
37
served as an adjunct to conventional therapy and should be used
only after an inadequate response to fluid resuscitation, high-dose
calcium salts, and pressors.
Hypoglycemia and hypokalemia secondary to insulin infusion
remain significant, although inconsistent, effects of this therapy.
Among reported cases, several patients who were hyperglycemic at
the onset of HIE remained so despite insulin infusions of up to
0.5 U/kg/h. Similarly, hypokalemia arose in only 4 of 11 patients.
Of those who developed hypokalemia, all remained asymptomatic,
and most of these patients went untreated (6). There have been no
reports of rebound in serum potassium concentrations once the insulin infusion is stopped. Because these patients are not thought to
have globally depleted stores of potassium, aggressive repletion of
K in asymptomatic patients may offer limited benefit.
CONCLUSIONS
As other reports have suggested, HIE is a safe and effective therapy for the treatment of calcium channel blocker intoxications (6).
At present, HIE is reserved as an adjunct to conventional therapy.
Future studies will determine if HIE therapy should be advanced to
initial therapy for calcium channel blocker poisoning.
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